Organic compounds

ABSTRACT

THIS INVENTION RELATES TO NOVEL PROCESSES FOR PREPARING LINCOMYCIN -4- MONOACYLATE COMPOUNDS AND 7-HALOGENATED LINCOMYCIN -4- MONOACYLATE COMPOUNDS, SELECTED FROM THE GROUP CONSISTING OF THE FREE BASES AND ACID ADDITION SALTS OF THE FORMULA:   1-R2,2-((2-(R-S-),4-HO,5-(AC-O-)TETRAHYDROPYRAN-6-YL)-   CH(-CH(-X)-CH3)-NH-CO-),4-R1-PYRROLIDINE   WHEREIN R IS ALKYL OF FROM ONE THROUGH SIX CARBON ATOMS; R1 IS ALKYL OF FROM ONE THROUGH EIGHT CARBON ATOMS, CYCLOALKYL OF FROM THREE THROUGH EIGHT CARBON ATOMS, OR ARALKYL OF UP TO TWELVE CARBON ATOMS; R2 IS ALKYL OF FROM ONE THROUGH EIGHT CARBON ATOMS OR HYDROGEN; X IS HYDROXY, CHLORINE, BROMINE OR IODINE; AND AC IS THE ACYL RADICAL OF A HYDROCARBON CARBOXYLIC ACID CONTAINING FROM TWO THROUGH EIGHTEEN CARBON ATOMS. IN THE ABOVE FORMULA I, THE VERTICAL WAVY LINE $ IS USED TO INDICATE THAT THE GROUP R1 CAN BE IN THE CIS POSITION (BELOW THE PLANE OF THE RING) OR IN THE TRANS POSITION (ABOVE THE PLANE OF THE RING), WITH RESPECT TO THE CARBONYL GROUP. THE HORIZONTAL WAVY LINE $ IS USED TO INDICATE THAT BOTH EPIMERS ARE TO BE INCLUDED IN THE GROUP, THE 7-(R) (OR D-ERYTHRO) CONFIGURATION AND THE 7-(S) (OR L-THREO) CONFIGURATION. THESE LINCOMYCIN-4-MONOACYLATE COMPOUNDS AND THEIR 7HALO COUNTERPARTS EMBRACED BY FORMULA I, ABOVE, CAN BE USED AS ANTIBACTERIAL AGENTS, FOR EXAMPLE TO INHIBIT THE GROWTH OF STAPHYLOCOCCUS AUREUS AND SARCINA LUTEA ON DENTAL AND MEDICAL EQUIPMENT CONTAMINATED WITH THESE ORGANISMS.

United States Patent US. Cl. 260-210 R 23 Claims ABSTRACT OF THE DISCLOSURE This invention relates to novel processes for preparing lincomycin 4 monoacylate compounds and 7-halogenated lincomycin 4 monoacylate compounds, selected from the group consisting of the free bases and acid addi tion salts of the formula:

wherein R is alkyl of from one through six carbon atoms; R is alkyl of from one through eight carbon atoms, cycloalkyl of .from three through eight carbon atoms, or aralkyl of up to twelve carbon atoms; R is alkyl of from one through eight carbon atoms or hydrogen; X is hydroxy, chlorine, bromine or iodine; and Ac is the acyl radical of a hydrocarbon carboxylic acid containing from two through eighteen carbon atoms. In the above Formula I, the vertical wavy line is used to indicate that the group R, can be in the cis position (below the plane of the ring) or in the trans position (above the plane of the ring), with respect to the carbonyl group. The horizontal wavy line is used to indicate that both epimers are to be included in the group, the 7-(R) (or D-erythro) configuration and the 7-(S) (or L-threo) configuration. These lincomycin-4-monoacylate compounds and their 7- halo counterparts embraced by Formula 1, above, can be used as antibacterial agents, for example to inhibit the growth of Staphylococcus aureus and Sarcina lutea on dental and medical equipment contaminated with these organisms.

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of US. application Ser. No. 861,195 filed Sept. 25, 1969, and now abandoned.

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BRIEF SUMMARY OF THE INVENTION The lincomycin-4-monoacylate compounds, including 7-dioxy-7-ha1oliucomycin-4-monacylate compounds of this invention are embraced by the formula CH 8 K Act) wherein R is alkyl of from one through six carbon atoms; R is alkyl of from one through eight carbon atoms, cycloalkyl of from three through eight carbon atoms, or aralkyl of up to twelve carbon atoms, situated below the plane of the pyrrolidine ring as drawn to give the cis configuration with respect to the carbonyl, or above the ring to give the trans configuration; R is alkyl of from one through eight carbon atoms, or hydrogen; X is hydroxy, chlorine, bromine or iodine, situated to the left of the vertical line as drawn to give the 7(R) configuration, or to the right to give the 7 (S) configuration; and Ac is the acyl radical of a hydrocarbon carboxylic acid of from two through eighteen carbon atoms; and the acid addition salts thereof.

Examples of alkyl of one through eight carbon atoms are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl and the isomeric forms thereof. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 2-methylcyclobutyl, 2,3-dirnethylcyclobutyl, 4-methylcyclobutyl, and 3-cyclopentylpropyl. Examples of aralkyl are benzyl, phenethyl, a-phenylpropyl, and a-naphthylmethyl. Suitable hydrocarbon carboxylic acid acyl radicals include radicals of (a) saturated or unsaturated straight or branched chain aliphatic carboxylic acids, for example, formic, acetic, propionic, butyric, isobutyric, tert-butylacetic, valeric, isovaleric, caproic, caprylic, decanoic, dodecanoic, acrylic, crotonic,

undecylenic, hexynoic, heptynoic, octynoic aicds and the like; (b) saturated or unsaturated, substituted, alicyclic carboxylic acids, for example, cyclobutanecarboxylic acid, cyclopentanecarboxylic acid, cyclopentenecarboxylic acid, methylcyclopentenecarboxylic acid, cyclohexanecarboxylic acid, dimethylcyclohexenecarboxylic acid, dipropylcyclohexanecarboxylic acid and the like; (c) saturated or unsaturated, substituted, alicyclic aliphatic carboxylic acids, for example, cyclopentaneacetic acid, cyclopentanepropionic acid, cyclopenteneacetic acid, cyclohexanebutyric acid, methylcyclohexaneacetic acid, and the like; ((1) aromatic carboxylic acids, for example, benzoic acid, toluic acid, naphthoic acid, ethylbenzoic acid, isobutylbenzoic acid, methylbutylbenzoic acid and the like; and (e) aromatic-aliphatic carboxylic acids, for example, phenyl-acetic acid, phenylpropionic acid, phenylvaleric acid, cinnamic acid, phenylpropiolic acid and naphthylacetic acid, and the like.

The novel lincomycin-4-monoacylate compounds of the above formula exist either in the non-protonated (free base) form or in the protonated (acid addition salt) form, depending on the pH of the environment. They form stable protonates, i.e., acid addition salts, on neutralization of the free base with suitable acids. Salts of lincomycin-4- monoacylate compounds can be made by neutralizing the free base with the appropriate acid to below about pH 7.0 and advantageously to about pH 2 to pH 6. Suitable acids for this purpose include hydrochloric, sulfuric, phosphoric, thiocyanic, fluosilicic, acetic, succinic, citric, lactic, maleic, fumaric, pamoic, cholic, palmitic, muic, camphoric, glu taric, glycolic, phthalic, tartaric, lauric, stearic, salicylic, 3 phenylsalicylic, phenylsalicylic, 3 methyl glutaric, orthosulfobenzoic, cyclohexanesulfamic, cyclopentanepropionic, 1,3 cyclohexanedicarboxylic, 4 cyclohexenecarboxylic, otadecenylsuccinic, octenylsuccinic, methanesulfonic, benzenesulfonic, helianthic, Reineckes, azobenzenesulfonic, octadecylsulfouric, picric, pamoic and like acids. Conversely, the free base of lincomycin-4-monoacylate compounds can be obtained from a salt, for example from the hydrochloride or sulfate salt, by dissolving or suspending the salt in buifer at about pH 5 to 7, preferably about pH 6, extracting with an immiscible organic solvent, for example chloroform, drying the extract, for example with anhydrous sodium sulfate, and removing the solvent by evaporation.

Addition salts of lincomycin-4-monoacylate compounds of this invention can be used for the same purpose as the free bases. They can also be used to upgrade the free bases, namely, by making acid addition salts of the free bases, subjecting them to purification procedures, and then converting the salts back to the free bases by neutralizing with an alkali or contacting withan anionic resin, advantageously to about pH 7.5 to 8.5, the free bases are upgraded.

In general, the acid addition salts of lincomycin-4- monoacylate compounds are the preferred forms for use, especially where alkaline aqueous solutions of the compounds are involved. This is because there is a tendency for the 4-monoacylates in the free base form to be somewhat unstable in mildly alkaline solutions, and prolonged exposure to solutions with pH values greater than about 7 to 7.5 should be avoided. At the other extreme, pH values of less than about 2 should be avoided in aqueous solutions of lincomycin-4-monoacylate compounds in either the free base or acid addition salt form, to minimize acidcatalyzed instability.

The novel processes of this invention are described in sections A, B, and C that follow.

(A) PROCESS USING SILYL ETHER PROTECTIVE GROUPS The free bases and acid addition salts of the 5-monoacylate compounds of the formula AcO wherein R, R R and Ac have the same meanipg as above and X is selected from the group consisting of Chlorine, bromine and iodine, are prepared by the steps comprising:

IV wherein R, R R and X have the same meaningas above, with a compound selected from a group consisting of a tetraalkyldisilizane tliHH wherein R is alkyl of one through four carbon atoms for example methyl, ethyl, propyl and butyl and isomeric forms thereof, or a hexaalkyldisilizane a l s Rs'si -N-|Sl R3 wherein R is as described above, to yield a corresponding bis-silyl ether compound of the formula R2 cu,

i.e., wherein the 2- and 3-hydroxyl groups in Formula IV have been silylated by a dialkylor trialkyl-silyl group, and wherein n is selected from the integers two and three and R, R R R and X have the same meaning as above;

(2) Mixing a thus produced corresponding compound resulting from Step (1) with a compound selected from the group consisting of an acyl halide and an acyl anhydride of a hydrocarbon carboxylic acid of from two through eighteen carbon atoms, in the presence of a tertiary amine base, to yield a corresponding compound of the formula II 2 cu,

wherein Ac, n, R, R R R and X have liEsame mean ing as above;

i.e. a lincomycin compound in which the 2,3, and 7-hydroxyl group have been silylated by a substituted-silyl group, in Step (1), a 2,3,7-tri-silyl ether-4-acylate (VI) st (R H osimgl w in Step (2) and a 2,3,7-trihydroxy-4-acylate (I) product in Step (3).

Lincomycins (IV) and their 7-halo counterparts (IV) undergo reaction with mild silanizing agents to give 2,3,7- tri-silyl ethers (V) with the former and 2,3-bis-silyl ethers (III) With the latter. Unexpectedly, the 4-hydroxyl group is not silylated. Hexaalk'yldisilizanes are the preferred reagents, while tetraalkyldisilizanes are also satisfactory. Trial-kylchlorosilanes are not preferred, due to the fact that they produce complete, rather than selective, silanization. Bistrialkylsilylacetamides are acceptable, although the reaction is not as specific as it is with hexaalkyldisilazanes. Trialkylsilylacetamides are unaccepetable since they produce random silanization.

Non-polar solvents are suitable for the silanization reaction. Chloroform is the preferred solvent, while acetone, acetonitrile, ether, etc. are satisfactory. Pyridine, dimethylformamide and other polar solvents are less desirable than the non-polar ones. The more polar solvents tend to permit some random silanization.

The optimum time and temperature for reaction of the starting compounds (IV) with the silanizing agents is from about 20 to about 200 hours at room temperature. Higher temperatures can be used with shorter times but some random silanization tends to occur at higher temperatures. Temperatures below room temperature are particularly acceptable, with specificity improved even though reaction time must be increased.

An excess of the disilizane reagent must be used in the reaction; when hexaalkyldisilazanes are employed, a 2 to 30 molar excess is acceptable. Gas chromatograms of the crude reaction mixture obtained from reaction of 20 g. of 7(S)-chloro-7-deoxylincomycin (IV) and 80 ml. of hexamethyldisilazane in 800 ml. of chloroform showed only one peak after 240 hours at room temperature. Under these conditions, 7(S)-chloro-7-deoxylincomycin-2,3- trimethylsilyl ether (III) is formed with only a trace of the corresponding 2,3,4-tris-trimethylsilyl ether.

The reaction between the starting compound (IV) and the disilazane will proceed with greater velocity by the addition of a catalyst, e.g., 0.001 to 1% of the corresponding chlorosilane, 0.001 to 10% of the corresponding silyl bis-acetamide, 0.001 to 10% of the corresponding silylimidazole or 0.001 to 10% of the corresponding silyltrifluoroacetamide.

The 4-acylation of the 2,3,7-tris-silyl ethers (V) and 2,3-bis-silyl ethers (III) in step (2) of the process is conducted by conventional methods, i.e., by mixing the ether (III) or (V) with an acyl halide or acyl anhydride of a hydrocarbon carboxylic acid in the presence of a teriary amine base. Suitable acyl halides of hydrocarbon carboxylic acids include acetyl chloride, propionyl chloride, triethylacetyl bromide, triethylbutyryl fluoride, 3,3- dimethyl butyryl bromide, tripropylpropionyl bromide; palmityl chloride, stearoyl bromide and the like. Suitable acyl anhydrides of hydrocarbon carboxylic acids include acetic, butyric, hexanoic, decanoic, palmitic and isomers thereof; acrylic, hexynoic, and the like; cyclopentanecarboxylic, dicyclohexanecarboxylic and the like; benzoic, toluic, naphthoic and the like; phenylacetic, cinnamic, naphthylacetic and the like. Suitable tertiary amine bases include pyridine, Z-methylpyridine, trimethylamine, dimethylethylamine, triethylamine and the like.

The silyl ether groups of the 2,3-bis-silyl ether-4-acylates (II) and 2,3,7-tris-silyl ether-4-acylates (IV) formed in Step (2) of the process are removed by treatment with an organic carboxylic acid having a pKa of from about 3 to about 6 for a period of about 1-20 hours at room temperature. Suitable organic carboxylic acids with their pKas at 25 C. enclosed in parentheses are: formic (3.77), propionic (4.88), n-valeric (4.81), n-heptylic (4.89), B- chlorpropionic (4.1), iodacetic (3.13), glycolic (3.83), trimethylacetic (5.02), vinylacetic (4.35), etc. The acid is removed under vacuum where possible, and the residue is dissolved or suspended in water (pH 6-7 and extracted with a solvent such as ether. Dry hydrogen chloride gas is added to precipitate a compound of Formula I wherein X is hydroxy, i.e., a lincomycin-4-acylate such as lincomycin-4-hexanoate hydrochloride (I); or a compound of Formula I wherein X is a halogen, namely, a 7-halo-7-deoxylincomycin-4-acylate such as 7(S)-7-deoxylincomycin-4- hexanoate hydrochloride (I). Recrystalization of the 4- acylates (I) can be carried out using suitable solvents.

The starting compounds of Formula IV wherein R, R and R have the same meaning as above and X is hydroxy, chlorine, bromine or iodine are known in the art. For example, the compound wherein R is methyl, R is trans-n-propyl, R is methyl and X is 7 (R)-hydroxy, is the Well known antibiotic lincomycin, also named methyl 6,8 dideoxy-6-(trans-1-methyl-4-propyl-L-Z-pyrrolidenecarboxamido) 1-thio-D-erythro-a-D-galactooctopyranoside. It is obtained as an elaboration product of a lincomycin-producing actinomycete in accordance with US. Pat. 3,086,912; it has the following structural formula Other unacylated lincomycin starting compounds (IV) having an OH group at the 4-position can be prepared by procedures disclosed in various patents as follows:

wherein Alkyl of one through six U.S. Pat. 3,380,992 (Specification carbon atoms. 12)

and Example MIGRATION OF THE CORRESPONDING 3- ACYLATE The free bases and acid addition salts of the 4-monoacylate compounds of the formula H wherein R, R R and Ac have the same meaning as above and X is selected from the group consisting of hydroxy, chlorine, bromine and iodine, are prepared :by mixing a corresponding compound of the formula xii (Ila) wherein R, R R Ac and X have the same meaning as in Formula 1, in a non-hydroxylic solvent with a strong acid.

The synthesis of lincomycin-4-monoacylates (I) and their 7-halo counterparts (I) by the acid catalyzed migration of the acyl group of the corresponding 3-monoacylates (11a) is achieved by treating the latter in an anhydrous non-hydroxylic solvent with between about 1 to about 20 equivalents of a strong acid for from about 1 to about 100 hours. Aqueous or hydroxylic solvents could be used, but are undesirable since the resulting solvolysis is a competing side reaction. The reaction is satisfactorily conducted at room temperature although higher or lower temperatures can be employed. The preferred solvent is a mixture of dimethylformamide and chloroform. Suitable other non-hydroxylic solvents (individually and in combination) that can be satisfactorily employed include (a) substituted amides (e.g., dimethyliformamide, dimethyl acetamide, diethylformamide and tetramethylurea), (b) sulfoxides (e.g., dimethylsulfoxide and sulfolane), (c) chlorinated hydrocarbons (e.g., chloroform, dichloroethane, dichloromethanc, carbon tetrachloride and methyl chloroform), (d) nitriles (e.g., acetonitrile, propionitrile and bu tyronitrile), (e) ethers (e.g., dicthylether, dioxane, tetrahydrofuran and methyl cellosolve), (f) esters (e.g., ethyl acetate, amyl acetate and methyl propionate), (g) ketones (e.g., acetone, methyl ethyl ketone and methyl isobutyl ketone), (h) nitroalkanes (e.g., nitromethane, nitropropane and nitroheptane), and the like. Polar solvents are preferred when using gaseous hydrogen chloride. Gaseous hydrogen chloride is the preferred acid; other acids, such as hydrogen bromide, p-toluenesulfonic acid, etc., can be used satisfactorily.

The 4-monoacylate products (I) are isolated by eX- traction employing conventional methods.

The gas chromatogram resulting from reaction of 1.5 mM. of lincornycin-3-hexanoate in 10 ml. of dimethylformamide and 10 ml. of chloroform, containing ml. of gaseous hydrogen chloride, shows that the migration of the 3-ester group to the 4-position is essentially complete in 48 hours at room temperature. The lincomycin- 4-hexanoate (I) product is present to the extent of about 70%, while only a minor amount of the lincomycin-3- hexanoate starting material remains.

(C) Process using the base catalyzed migration of the corresponding 2- or 3-acylate The free bases and acid addition salts of the 4-monoacylate compounds of the formula Act) wherein R, R R and Ac have the same meaning as above and X is selected from the group consisting of hydroxy, chlorine, bromine and iodine, are prepared by the steps comprising:

(1) Mixing a corresponding 3-acylate compound of the Formula IIa, or a corresponding 4-acylate compound of the Formula IIb has a lower partition coefficient than the 2- and 3-mon0- acylates and, therefore, can be separated from the isomeric esters by selective extraction.

Non-polar solvents, such as chloroform are preferred. Although hydroxylic or aqueous solvents may be used. Strongly basic tertiary amines are preferred such as trimethylamine, triethylamine, etc., although inorganic bases such as sodium hydroxide and the like may be used. Pyridine is not sufliciently basic to catalyze the reac tion.

The molar ratio of the tertiary amine to the 3-monoacylate (Ila) must be greater than one, with the preferred molar ratio of amine to acylate being about three. The reaction is best carried out at room temperature, although temperatures between about C. and about 60 C. are operable.

The gas chromatogram resulting from reaction with three parts of triethylamine, one part of lincomycin-3- hexanoate (11a) and 20 parts of chloroform for 144 hours, shows a yield of about 20% of lincomycin-4- hexanoate (I). A chromatogram resulting from a reaction wherein tripropylamine is substituted for triethylamine in the foregoing system, shows the formation of about 40% of lincomycin-4-hexanoate (I).

In the instances where the desired lincomycin 4-monoacylate compound of Formula I is a member of the group in which R is hydrogen, i.e., in the case of 1'-desmethyl lincomycin compounds, simultaneous undesirable acylation at 1'-N is prevented by first protecting the l'-N atom with a protective group removable by hydrogenolysis. Suitable such groups are trityl, i.e., triphenyl-methyl, diphenyl-(p-methoxyphenyl)methyl, bis (p-methoxyphenyl)-phenylmethyl, benzyl, or p-nitrobenzyl and hydrocarbyloxycarbonyl groups. Examples of the latter are tertiary-butoxycarbonyl; benzyloxycarbonyl groups of the formula 1? wQ-omo owherein W is hydrogen, nitro, methoxy, chloro, or bromo, for example, carbobenzoxy, p-nitrocarbobenzoxy, p-bromo-, and p-chlorocarbobenzoxy-; and phenyloxycarbonyl groups of the formula wherein W is hydrogen, allyl, or alkyl of not more than 4 carbon atoms, such as phenyloxycarbonyl, p-tolyloxycarbonyl, p-ethylphenyloxycarbonyl, and p-allylphenyloxycarbonyl and the like. After 4-monoacylation of the 1-protected lincomycin compound by the process of this invention, the protective group is replaced by hydrogen by hydrogenolysis, according to the art, to yield the 4-monoacylate ester of the 1'-hydrogen lincomycin compound.

Lincomycin-4-monoacylate compounds of Formula I, herein defined, and their acid addition salts are valuable antibacterial agents. The compounds, for example lincomycin-4-hexanoate hydrochloride (I), inhibit the growth of S. lutea and S. aureus and therefore are useful as disinfectants on various dental and medical equipment contaminated with these organisms. Similarly, for example 1'-desmethyllincomycin-4-butyrate, they can be used to disinfect washed and stacked food utensils contaminated with such organisms. The novel 7-halogenated or hydroxylated lincomycin-4-monoacylate compounds (I) afforded by the processes of the present invention have the additional advantages noted previously.

DETAILED DESCRIPTION It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described herein, as obvious modifications and equivalents will be apparent to one skilled in 10 the art', and the invention is therefore to be limited only by the scope of the appended claims.

EXAMPLE 1 A solution of 10 g. of 7(S)-chloro-7-deoxylincomycin (IV) [also named methyl 7-chloro 6,7,8 trideoxy 6 (trans-1-methyl-4-propyl L 2 pyrrolidinecarboxamido)-1-thio L threo-a-D-galactooctopyranoside] (prepared as in Belgian Pat. 676,154) in 800 ml. of chloroform is mixed with ml. of hexamethyldisilizane. After about 10 days at room temperature the solution is concentrated under high vacuum at about 40 C. to give a viscous residue of 7(S)-chloro-7-deoxylincomycin-2,3-bis (trimethylsilyl) ether (III). The clear viscous material is dissolved in 300 ml. of pyridine and mixed with 30 ml. of hexanoic anhydride. After about 7 days at room temperature the solution is concentrated under high vacuum to give a viscous residue of 7(S)-ch1oro-7-deoxylincomycin-4-hexanoate-2,3-bistrimethylsilyl ether (11). The residue is dissolved in 200 ml. of 80% acetic acid and allowed to stand at room temperature for about 3 hrs. The solvent is removed under high vacuum at about 45 C. and the resulting colorless viscous residue dissolved in 200 ml. of ether. The ethereal solution is dried with sodium sulfate and dry hydrogen chloride bubbled in to precipitate 5 g. of crude 7(S)-chloro-7-deoxylincomycin- 4-hexanoate hydrochloride (1). The compound is dissolved in 200 ml. of a 0.2 M phosphate-citrate buffer of pH 5.5.

' The resulting solution is extracted with 200 ml. of ether and the ether extract dried with sodium sulfate. Addition of gaseous hydrogen chloride to the ether extract precipitates 2.1 g. of product (I), which is isolated and then stirred with 50 ml. of acetonitrile. The insoluble compound is isolated by filtration to give 1.2 g. of pure 7(S)- chloro-7-deoxylincomycin-4-hexanoate hydrochloride (I).

Analysis.-Calcd. for C H N O SCl (percent): C, 51.51; H, 7.93; N, 5.01; S, 5.73; Cl,.12.67. Found (corrected for 0.83% H O) (percent): C, 51.28; H, 7.86; N, 4.72; H, 5.69; CI, 12.50.

7(S)-chloro-7-deoxylincomycin-4-hexanoate hydrochloride has a plate antibacterial activity equivalent to 41 micrograms of lincomycin per mg. using S. lutea as test organism. Its relative molar CD is 0.27 times lincomycin when administered subcutaneously and 0.14 times lincomycin when given orally to mice infected with S. aureus.

7 (S)-chloro-7-deoxylincomycin-4-hexanoate hydrochloride can be converted to the free base, 7(S)-chloro-7- deoxylincomycin-4-hexanoate, by suspending in 0.1 M potassium phosphate buffer, pH 6.5, extracting with chloroform or methylene chloride, drying the extract with anhydrous sodium sulfate and evaporating.

The 7( S) -chloro-7-deoxylincomycin-4-hexanoate (I) is promptly converted to other salts by contacting with other acids as previously disclosed.

Following the procedure of Example 1 but substituting 7(S)-chloro-7-deoxylincomycin hydrochloride (IV) for its free base, yields 7(S)-chloro-7-deoxylincomycin-4-hexanoate hydrochloride (I).

Following the procedure of Example 1 but substituting another hexaalkyldisilizane, for example hexaethyldisili- Zane, hexapropyldisilizane or hexabutyldisilizane, for hexamethyldisilizane, also yields 7 (S)-chloro-7-deoxylincomycin-4-hexanoate hydrochloride (I).

Following the procedure of Example 1 but substituting a tetraalkyldisilizane, e.g. tetramethyl-, tetraethyl-, tetra-' propylor a tetrabutyl-disilizane for hexamethyldisilizane,

also produces 7(S)-chloro-7-deoxylincomycin-4-hexanoate hydrochloride (I).

Following the procedure of Example 1 but substituting 7(R)-chloro-7-deoxylincomycin (IV) as the starting material, yields 7(R) -chloro-7-deoxylincomycin-4-hexanoate hydrochloride (I).

EXAMPLE 2 Lincomycin-4-hexanoate hydrochloride (I) Following the procedure of Example 1 but substituting for the 7(S)-chloro-7-deoxylincomycin (IV) employed therein, lincomycin (IV) [also named 6,8-dideoxy-6- (trans 1 methyl-4-propyl-L-2-pyrrolidinecarboxamido)- 1-thio-D-erythro-a-D-galacto-octopyranoside] (prepared as in US. Pat. 3,086,912), yields lincomycin-4-hexanoate hydrochloride (I).

A solution of 1 g. of lincomycin (IV) in 80 ml. of acetone is mixed With 8 ml. of tetramethyldisilizane. After about 10 days at room temperature the solution is concentrated under high vacuum at about 40 C. to give a viscous residue of lincomycin 2,3,7-tris-(dimethylsilyl) ether (V). The clear viscous material is dissolved in 30 ml. of pyridine and mixed with 3 ml. of hexanoic anhydride. After about 7 days at room temperature the solution is concentrated under high vacuum to give a viscous residue of lincomycin-4-hexanoate-2,3,7-tris-(dimethylsilyl) ether (VI). The residue is dissolved in 20 ml. of propionic acid and 4 ml. water and allowed to stand at room temperature for about 3 hrs. The solvent is removed under high vacuum at about 45 C. and the resulting colorless viscous residue dissolved in 20 ml. of ether. The ethereal solution is dried with sodium sulfate and dry hydrogen chloride bubbled in to precipitate crude lincomycin-4-hexanoate hydrochloride (I). The compound is dissolved in 20 ml. of 0.02 M phosphate-citrate buffer of pH 5.5. The resulting solution is extracted with 20 ml. of ether and the ether extract dried with sodium sulfate. Addition of hydrogen chloride to the ether extract gives the product (I) which is isolated and then stirred with 5 ml. of acetonitrile. The insoluble compound is isolated by filtration to give pure lincomycin-4-hexanoate hydrochloride (1).

Lincomycin-4-hexanoate hydrochloride (I) is converted to lincomycin-4-hexanoate (I) by treatment equivalent to that described for the 7(S)-chloro analog in Example 1.

EXAMPLE 3 Lincomycin-4-acylate and 7 (S or R)-halo-7-deoxylincomycin-4-acylate acid addition salts and free bases (1) The corresponding lincomycin-4-acylate and 7 (S or R)- halo-7-deoxylincomycin4-acylate acid addition salts and free bases (I) are obtained by substituting for the hexanoic anhydride employed in Examples 1 and 2 (and the paragraphs thereafter) the anhydrides of the following hydrocarbon carboxylic acids: acetic, butyric, pentanoic, hexanoic, heptanoic, octanoic, nonanoic, decanoic, dodecanoic, tetradecanoic, hexadecanoic (palmitic), octadecanoic, and isomers thereof: acrylic, crotonic, undecylenic, hexynoic, heptynoic, octynoic acids and the like; saturated or unsaturated, substituted, alicyclic carboxylic acids, for example, cyclobutanecarboxylic acid, cyclopentanecarboxylic acid, cyclopentecarboxylic acid, methylcyclopentenecarboxylic acid, cyclohexanecarboxylic acid, dimethylcyclohexenecarboxylic acid, dipropylcyclohexanecarboxylic acid and the like; cyclopentaneacetic acid, cyclopentanepropionic acid, cyclopenteneacetic acid, cyclohexanebutyric acid, methylcyclohexaneacetic acid, and the like; benzoic acid, toluic acid, naphthoic acid, ethylbenzoic acid, isobutylbenzoic acid, methylbutylbenzoic acid and the like; phenylacetic acid, phenylpropionic acid, phenylvaleric acid, phenylpropiolic acid and naphthylacetic acid, and the like; cyclohexanecarboxylic acid, 2,6-dimethyl-3-cyc1ohexane-l-carboxylic acid, 3,4-dipropylcyclohexanecarboxylic acid, cyclopentaneacetic acid, 3-cycl0- pentylpropionic acid, 4-cyclohexylbutyric acid (Z-methylcyclohexyl) acetic acid, p-ethylbenzoic acid, p-isobutylbenzoic acid, 3-methyl-4-butylbenzoic acid, 3-phenylpropionic acid, S-phenylvaleric acid, cinnamic acid, 3- phenylpropiolic acid, (1-naphtyl)-acetic acid, and the like EXAMPLE 4 Lincomycin-4-acylate and 7(S or R)-ha1o-7-deoxylincomycin-4-acy1ate acid addition salts and free bases (1) The corresponding 1incomycin-4-acylate and 7(S or R)- halo-7-deoxylincomycin-4-acylate acid addition salts and free bases (I) are obtained by substituting for the hexanoic anhydride employed in Examples 1 and 2 (and the paragraphs thereafter) the following halides of hydrocarbon carboxylic acids (i.e., acyl halides): propionyl chloride, trimethylacetyl chloride (pivalyl chloride), triethylacetyl chloride, trimethylpropionyl chloride, trimethylbutyryl chloride, 2,2-, 2,3- and 3,3-dimethylbutyryl chloride, tributylpropionyl bromide, triethylbutyryl fluoride, tripropylpropionyl fluoride, palmityl chloride, steoroyl bromide and the like.

EXAMPLE 5 Lincomycin 4 acylate and 7(S or R) halo 7 deoxylincomycin-4-acylate acid addition salts and free bases (1) Following the procedures of Examples 1 through 4 (and the paragraphs thereafter) and substituting other lincomycin derivatives (IV) and other anhydrides and halides of hydrocanbon carboxylic acids for the 7 (S)-chloro-7- deoxylincomycin (IV) and lincomycin (IV) and hexanoic anhydride employed therein, and including hydrogenolysis as described in US. Patent 3,880,992 to remove the protective carbobenzoxy group when appropriate, such as: (l) 7(S) bromo 7 deoxylincomycin (IV) [methyl 7 bromo 6,7,8 trideoxy 6 (trans-l-methyl-4-npropyl-L 2 pyrrolidinecarboxamido) 1 thio-L- threo-a-D-galacto-octopyranoside] and pentanoic anhydride,

(2) 1 desmethyl 1' carbobenzoxy 4 despropyl- 4' n-pentyl 7(S)-chl0ro 7-deoxylincomycin [methyl 7 chloro 6,7,8 trideoxy 6 (trans-l-carbobenzoxy- 4 n-pentyl-L 2 pyrrolidine carboxamido)-l-thio-L- threo-a-D-galacto-octopyranoside, and hexanoic anhydride; and hydrogenolysis,

(3) 1 desmethyl l isobutyl 7(R)-ch1oro-7-deoxylincomycin (IV) [methyl 7 chloro 6,7,8 trideoxy- 6 (trans 1 isobutyl 4 n-propyl-L-2-pyrrolidinecarboxamido) l thio D erythro-ot-D-galactooctopyranoside] and heptanoic anhydride,

(4) 4' despropyl 4' heptyl 1 desmethyl 1'-cyclohexyl 7(R)-chloro 7 deoxyallolincomycin (IV) [methyl 7 chloro 6,7,8 trideoxy 6 (cis-1-cyclo hexyl 4 heptyl-L-Z-pyrrolidinecarboxamido)-1-thio- D-erythro-a-D-galacto-octopyranoside] and octanoic anhydride,

(5) 4 despropyl 4' n-pentyl 1' desmethyl 1'- canbobenzoxy 7(S)-chloro 7 deoxylincomycin hydrochloride [methyl 7 chloro 6,7,8 trideoxy 6- (trans 1 carbobenzoxy 4 n-pentyl-L-Z-pyrrolidinecarboxamido) 1 thio-L-threo-a-D-galactooctopyranoside hydrochloride] and palmityl chloride; and hydrogenolysis,

(6) 1 desmethyl 1' carbobenzoxy 7 (S)-chloro-7- deoxylincomycin hydrochloride [methyl 7 chloro-6, 7,8 trideoxy 6 (trans 1 carbobenzoxy-4-n-propyl- L 2 pyrrolidinecarboxamido) 1 thio-L-threo-a- D-galacto-octopyranoside hydrochloride] and hexanoic anhydride; and hydrogenolysis,

(7) 1 desmethyl 1' carbobenzoxy 7(S)-chloro- 7 deoxylincomycin [methyl 7 chloro 6,7,8 trideoxy 6 (trans 1 carbobenzoxy 4 n-propyl-L- 2 pyrrolidinecarboxamido) 1 thio-L-threo-u-D- galacto-octopyranoside] and tetradecanoic anhydride; and hydrogenolysis,

(8) S-desmethyl-S-ethyl 7(S)-chloro-7-deoxylincomcyin citrate (IV) [ethyl 7 chloro 6,7,8 trideoxy 6- (trans 1 methyl 4 n-propyl-L-2-pyrrolidinecarboxamido) 1 -thio-L-threo-u-D-galacto-octopyranoside citrate] and heptadecanoic anhydride,

(9) 1 desmethyl 1' ethyl 7(S)-chloro-7-deoxylincomycin (IV) [methyl 7 chloro 6,7,8-trideoxy-6- (trans 1 ethyl 4-n-propyl-L-2-pyrrolidinecarboxamido) 1 thio-L-threo-a-D-galacto-octopyranoside] and tri butylpropionyl bromide,

(10) 1' desmethyl 1' ethyl 7(S)-chloro7-deoxylincomycin (IV) [methyl 7 chloro 6,7,8 trideoxy-6- (trans 1 -ethyl 4 n-prpyl-L-2-pyrrolidinecarboxamido) 1 thio-L-threo-u-D-galacto-octopyranoside] and decanoic anhydride,

(11) 4 despropyl 4' n-pentyl 1 desmethyl-l'-carbobenzoxy 7(S)-chloro 7 deoxylincomycin [methyl 7 chloro 6,7,8 -trideoxy 6 (trans 1 carbobenzoxy 4 n-pentyl-L-Z pyrrolidinecarboxamido)- 1 thio L threo-u-D-galacto-octopyranoside] and triethylacetyl chloride; and hydrogenolysis,

(12) 4' despropyl 4' n-pentyl-l-desmethyl-l-carbobenzoxy 7(S)-chloro 7 deoxylincomycin [methyl 7 chloro 6,7,8 trideoxy 6 (trans-l-carbobenzoxy- 4 n-pentyl-L 2 pyrrolidinecarboxamido)-1-thio-L- threo-a-D-galacto-octopyranoside1 and palmityl chloride and hydro genolysis,

(13) 1' desmethyl 4' despropyl-1',4'-diisobutyl-7 (S)- chloro 7 deoxylincomycin (IV) [methyl 7-chloro- 6,7,8 trideoxy 6 (trans 1,4 diisobutyl-L-2- pyrrolidinecarboxamido) 1 tl1io-L-threo-a-D-galactooctopyranoside] and lauroyl chloride,

(14) 1' desmethyl 1' carbobenzoxy 7(S)-chloro-7- deoxylincomycin phosphate [methyl 7 chloro 6,7,8- trideoxy 6 (trans 1 carbobenzoxy 4 n-propyl- L 2 pyrrolidenecarboxamido) 1 thio-L-threo-u- D'-galacto-octopyranoside phosphate] and pentanoic anhydride; and hydrogenolysis,

(15) 1' desmethyl 1' carbobenzoxy 7 (R)-bromo- 7 deoxyallolincomycin [methyl 7 bromo 6,7,8-trideoxy 6 (cis 1 carbobenzoxy 4 pro-pyl-L-2- pyrrolidenecarboxamido) 1 thio D-erythro-a-D- galacto-octopyranoside] and palmityl chloride; and bydrogenolysis,

(16) S-desmethyl-S-propyl-l'-desmethyl-1-carbobenzoxy- 7(S)-chloro-7-deoxylincomycin [propyl 7-chloro-6,7,8- trideoxy 6 (trans-1-carbobenzoxy-4-propyl-L-2pyrrolidenecarboxamido) 1 thio-L-threo-ot-D-galactooctopyranoside] and hexynoic anhydride; and hydrogenolysis,

(17 1'-desmethyl- 1-ethyl-4-despropyl-4'-n-pentyl-7 (S) chloro-7-deoxylinoomycin (IV) [methyl 7-chloro-6,7,8- trideoxy 6 (trans-l-ethyl-4-n-pentyl-L-2-pyrrolidenecarboxamido) l thio L threo-a-D-galacto-octopyranoside] and tetradecanoic anhydride,

(18) lincomycin (IV) [6,8-dideoxy-6-(trans-1-methyl-4- propyl-L-2-pyrrolidinecarboxamido) l-thio-D-erythroa-D-galacto-octopyranoside] and dodecanoic anhydride,

(19) lincomycin (IV) and palmityl chloride,

(20) 1-desmethyl-1'-carbobenzenoxy-lincomycin [6,8-dideoxy 6 (trans-1-carbobenz0xy-4-propyl-L-2-pyrrolidenecarboxamido) 1 thio D erythro-a-D-galactooctopyranoside] and nonanoic anhydride; and hydrogenolysis, etc.,

yields, respectively,

( 1 7 (S -bromo-7-deoxylinoomycin-4-pentanoate (I) (2) 1'-desmethy1-4-despropyl 4'-n-pentyl-7(S)-chloro-7- deoxylincomycin-4-hexanoate (I),

(3) 1' desmethyl-1-isobutyl-7(R)-chloro-7-deoxylincomycin-4-heptanoate (I),

(4) 4'-despropyl-4'-heptyl-1'-desmethyl 1' cyclohexyl- 7 (R) -chloro-7-deoxyallolincomycin-4-octanoate (I) (5) 1'-desmethyl-4'-despropyl-4'-n-pentyl-7 (S) chloro-7- deoxylincomycin-4-palmitate hydrochloride (I),

(6) 1-desmethyl-7 (S)-chloro-7-deoxylincomycin-4 hexanoic hydrochloride (1),

(7 1-desmethyl-7 (S) -chloro-7-deoxylincomycin-4-tetradecanoate (I),

(8) S-desmethyl-S-ethyl-7 (S) chloro-7-deoxylincomycin- 4-heptadecanoate citrate (I),

(9) 1-desmethyl-1'-ethyl-7 (S)-chloro 7 deoxylincomycin-4-tributylpropionate (I) (l0) 1 desrnethyl-1'ethyl-7 (S)-chloro-7-deoxylincomycin-4-decanoate (I),

(11) 4'-despropyl-4'-n-pentyl-7(8)-chloro 7 deoxylincomycin-4-triethyl acetate (I),

(12) 1'-desmethyl-4-despropyl-4'-n-pentyl-7 (S) chloro- 7-deoxylincomycin-4-palmitate (I),

(13) 1'-desmethyl-4'-despropyl- 1',4' diisobutyl 7(S)- chloro-7-deoxylincomycin-4-lauroate (I),

( 14) 1'-desmethyl-7 (S) -chloro-7-deoxylincomycin-4pentanoate (I),

(15 1'-desmethyl-7(R)-bromo-7-deoxylincomycin-4-palmitate (I),

(16) S-desmethyl-S-propyl-l'-desmethyl-7(S)-chloro 7- deoxylincomycin-4-hexyn0ate (I),

(17) 1'-desmethyl-1-ethyl-4'-despropyl-4'-n-penty1-7 (S)- chloro-7-deoxylincomycin-4-tetradecanoate (I),

( 18) lincomycin-4-dodecanoate (I),

(19) lincomycin-4-palmitate (I),

(20) 1-desmethyl-lincomycin-4-nonanoate (I), etc.

Following the procedure of the immediately preceding paragraph but substituting for pyridine (employed in Examples 1 and 2), another amine base such as 3-methylpyridine, 4-propylpyridine, S-butylpyridine, 3-methyl-4- ethylpyridine, 3,4-dibutylpyridine, 3-ethyl-4-isopropylpyridine, 3-propyl-4-isobutylpyridine, 3-ethyl-5-propylpyridine, 3,5-dimethylpyridine, 3-isopropyl-5-sec. butylpyridine, 3,4,5-trimethylpyridine, 3,4-dibutyl-5-propylpyridine, 3-ethyl-4-propyl-5butylpyridine, 3,5-diethyl-4- methylpyridine, etc., also yields the compounds prepared in the aforesaid paragraph.

EXAMPLE 6 Lincomycin-4-hexan0ate hydrochloride (I) A solution of 50 g. of lincomycin hydrochloride in 200 ml. of N,N-di-methylformamide is mixed with 60 ml. of tripropylamine and 50 ml. of hexanoic anhydride. After about 24 hours at room temperature, gas chromatographic analysis shows that about 91% of lincomycin-Z-hexanoate hydrochloride (11a) is formed. The reaction is terminated by the addition of 20 ml. of water and the solution is concentrated to a viscous liquid under high vacuum at about 40 C. The resulting brown residue is dissolved in 1000 ml. of water and the solution extracted with 100 ml. of ether. The aqueous phase is mixed with 200 ml. of water containing 56.3 g. of disodium hydrogen phosphate and 20.4 g. of citric acid (monohydrate). The aqueous phase is extracted with 1000 ml. of chloroform. The chloroform extract is washed three times with 2 liter portions of water containing 57.2 g. of disodium hydrogen phosphate and 20.4 g. of citric acid (monohydrate) per liter. The chloroform layer is dried over sodium sulfate and the solvent removed under vacuum. The clear viscous residue is dissolved in 800 ml. of ether and the product precipitated by the addition of gaseous hydrogen chloride. It is isolated by filtration, washed with ether and dried by passing nitrogen through the filter to give 25.1 g. of lincomycin-3-hexanoate hydrochloride (IIa). 'The identity of the product compound is confirmed by its nuclear magnetic resonance (NMR) spectrum.

Analysis.-Calcd. for C H N O SCl (percent): C, 53.27; H, 8.38; N, 5.18; S, 5.93; Cl, 6.55. Found (corrected for H O content) (percent): C, 53.67; H, 8.60; N, 5.12; S, 5.73; Cl, 6.34. (H O, 2.40).

One liter of hydrogen chloride gas is shaken with 100 ml. of dimethylfonmamide and ml. of chloroform.

Into this mixture g. of lincomycin-3-hexanoate hydrochloride (lla) is dissolved and the solution allowed to stand at room temperature for about 8 days. The reaction mixture is stirred with 20 g. of sodium sulfate and the supernatant poured into 1500 ml. of ether. The resulting sticky precipitate is isolated and dissolved in 200 ml. of chloroform. The chloroform solution is extracted with 200 ml. of 0.2 M phosphate-citrate buffer of pH 5.5 and the chloroform layer evaporated to dryness under vacuum. The resulting viscous residue is dissolved in 200 ml. of ether and, upon addition of hydrogen chloride gas, 5.2 g. of pure lincomycin-4-hexanoate hydrochloride (I) is obtained.

Analysis.-Calcd. for C H N O SCl (percent): C, 53.27; H, 8.38; N, 5.18; S, 5.93; Cl, 6.55. Found (corrected for 1.38% H O) (percent): C, 52.91; H, 8.38; N, 4.40; S, 5.93; CI, 6.61.

Lincomycin-4-hexanoate hydrochloride (I) is converted antibacterial activity equivalent to 86 micrograms of lincomycin per mg. using S. lutea as test organism. Its relative molar CD is 0.24 times lincomycin when administered subcutaneously and 0.15 times lincomycin when given orally to mice infected with S. aureus.

Lincomycin-4-hexanoate hydrochlorde (I) is converted to its free base in the manner described in the second paragraph following Example 2.

EXAMPLE 7 7 (S) -chloro-7-deoxylincomycin-4-hexanoate hydrochloride (1) 52 g. of 7(S)-chloro-7-deoxylincomycin hydrochloride is dissolved in 200ml. of N,N-dimethylformamide and 60 ml. of tributylamine and 107 g. of hexanoic anhydride are added. After about 30 hours at room temperature the reaction is terminated by addition of 100 mls. of water. The resulting diluted reaction mixture is extracted with 100 ml. ether. The aqueous phase is mixed with 200 ml. of water containing 56.3 g. of disodium hydrogen phosphate and 20.4 g. of citric acid (monohydrate). The aqueous phase is extracted with 1000 ml. of ether. The ether extract is washed three times with 2-1iter portions of water containing 57.2 g. of disodium hydrogen phosphate and 20.4 g. of citric acid (monohydrate) per liter. The ether layer is dried over sodium sulfate and the solvent removed under vacuum. The residue is dissolved in 800 ml. of ether and the product precipitated by the addition of gaseous hydrogen chloride. It is isolated by filtration, washed with ether and dried by passing nitrogen through the filter to give 7(S)-chloro-7-deoxylincomycin-3-hexanoate hydrochloride (11a).

Following the procedure of Example 6 but substituting 7(S) chloro-7-deoxylincomycin-3-hexanoate hydrochloride (IIa) as starting material, yields 7(S)-chloro-7-deoxylincomycin-4-hexanoate hydrochloride (I).

7 (S)-chloro-7-deoxylincomycin-4-hexanoate hydrochloride (I) is converted to its free base in the manner described in the second paragraph following Example 1.

EXAMPLE 8 Lincomycin-4-acylates and 7(S or R)-halo-7-deoxylincomycin-4-acylate acid addition salts and free bases (1) Following the procedures of Examples 6 and 7 (and the paragraphs thereafter) and substituting other lincomycin derivatives (Ila) and other strong acids for the lincomycin-3-hexanoate hydrochloride (11a) and 7(S)- chloro-7-deoxylincomycin 3 hexanoate hydrochloride (11a) and hydrogen chloride employed therein, such as (1) 7(S)-bromo-7-deoxylincomycin-3-octanoate (11a) and hydrogen bromide,

(2) 7 (R)-iodo-7-deoxylincinomycin-3-propionate (Ila) and hydrogen iodide,

(3) 7(S)-chloro-7-deoxylincomycin-3-decanoate (11a) and p-toluenesulfonic acid,

(4) 1'-desmethyl-l-isobutyl-7 (R)-chloro-7-deoxylincomycin-3-pentanoate (11a) and sulfuric acid,

(5) 1-desmethyl-4'-despropyl-4'-n-pentyl-7 (S) -chloro- 7-deoxylincomycin-3-pa1mitate hydrochloride (11a) and nitric acid,

(6) S-desmethyl-S-ethy1-7(S)-chloro-7-deoxylincomycin-S-tetradecanoate (11a) and sulfuric acid,

(7) 4-despropyl-4-n-pentyl-7 (S -chloro-7-deoxylincomycin-3-laurate (Ila) and hydrogen bromide,

(8) lincomycin-3-nonanoate (11a) and p-toluenesulfonic acid,

(9) lincomycin-3-heptadecanoate (Ila) and hydrogen bromide,

(10) 1-desmethyl-lincomycin-3-octanoate (Ila) and nitric acid, etc.,

yields, respectively,

(1 7 (S -bromo-7-deoxylincomycin-4-octanoate hydrobromide (I),

(2) 7(R)-iodo-7-deoxylincomycin-4-propionate hydroiodide (I),

(3) 7(S)-chloro-7-deoxylincomycin-4-decanoate ptoluenesulfonic acid (I),

(4) 1-desmethyl-1'-isobutyl-7 (R) -ch1oro-7-deoxylincomycin-4-pentanoate sulfate (1),

(5 l-desmethyl-4'-despropyl-4-n-pentyl-7 (S) -chloro- 7-deoxylincomycin-4-palmitate nitrate (I),

(6) S-desmethyl-S-ethyl-7 (S -chloro-7-deoxylincomycin-4-tetradecanoate sulfate (I),

(7) 4'-despropyl-4-n-pentyl-7 (S) -chloro-7-deoxylincomycin-4-1aurate hydrobromide (I),

(8) liucomycin-4nonanoate p-toluenesulfonic acid (I),

(9) lincomycin-4'-heptadecanoate hydrobromide (I),

( 10) 1-desmethyl-lincomycin-4-octanoate nitrate (I),

etc.

EXAMPLE 9 Lincomycin-4-hexanoate hydrochloride (I) A solution of 8 g. of lincomycin-3-hexanoate hydrochloride (IIa) in a mixture of ml. of chloroform and 20 ml. of triethylamine is allowed to stand at room temperature for about 3 days. The solvent, containing a mixture of the 2-,3- and 4-monohexan0ates of lincomycin hydrochloride, is removed under vacuum at about 60 C. and the residue dissolved in ml. of 0.2 M phosphate-citrate buffer of pH 3. The solution is extracted with three 250 ml. portions of chloroform. The pH of the aqueous layer is adjusted to 6.2 by the addition of sodium carbonate. The aqueous solution is extracted twice with 100 ml. of chloroform and the combined extracts concentrated to a viscous residue under vacuum at about 60 C. The residue is dissolved in 100 ml. of ether and the solution treated with gaseous hydrogen chloride to precipitate the hydrochloride salt of lincomycin-4-hexanoate (I). The compound is isolated by filtration, washed with ether, and dried by passing nitrogen through the filter to give 0.6 g. of pure lincomycin-4-hexanoate hydrochloride (I).

Analysis.Calcd. for C H N O SCl (percent): C, 53.27; H, 8.38; N, 5.18; S, 5.93; Cl, 6.55. Found (corrected for 0.84% E 0) (percent): C, 52.77; H, 8.41; N, 4.99; S, 6.01; CI, 6.80.

Lincomycin-4-hexanoate hydrochloride (1) is converted to its free base in the manner described in the second paragraph following Example 2.

EXAMPLE l0 7 (S) -chloro-7-deoxy1incomycin-4-hexanoate hydrochloride (1) Following the procedure of Example 9 but substituting 7 (S)-chloro-7-deoxylincomycin-3-hexanoate hydrochloride (IIa) as starting material, yields 7(S)-chloro-7- deoxylincomycin-4-hexanoate hydrochloride (I).

7 (S) chloro 7 deoxylincomycin 4 hexanoate hydrochloride (I) is converted to its free base in the manner described in the second paragraph following Example 1.

EXAMPLE 11 Lincomycin 4 acylates and 7(S or R) halo 7 deoxylincomycin 4 acylate acid addition salts and free bases (1) Following the procedures of Examples 9 and 10 (and the paragraphs thereafter) and substituting other lincomycin derivatives (Ha) and other strong tertiary amine bases for the lincomycin 3 hexanoate hydrochloride (Ha) and 7(S) chloro 7 deoxylincomycin hydrochloride (Ha) and triethylamine employed therein, such yields, respectively,

( 1) 7 (S) -chloro-7-deoxylincomycin-4-heptanoate (I),

(2) 7(R)-bromo-7-deoxylincomycin-4-dodecanoate hydrochloride (I),

(3) 7 (S)-iodo-7-deoxylincomycin-4-nonanoate hydrochloride (I),

(4) 1-desmethyl-1'-butyl-7 (R)-chloro-7-deoxylincomycin-4-octanoate (I),

(5) 1-desmethyl-1'-ethyl-7(S)-bromo-7-deoxylincomycin-4-tributyl butyrate (I),

(6) 1'-desmethyl-4-despropyl-1',4-diisobutyl-7(S)- chloro-7-deoxylincomycin-4-heptadecanoate hydrochloride (I),

(7) S-desmethyl-S-propyl-1'-desmethyl-7(8)-chloro- 7-deoxylincomycin-4-hexanoate (I),

(8) lincomycin-4-laurate hydrochloride (1),

(9) lincomycin-4-propionate hydrochloride (1),

' (10) 1'-desmethyl-lincomycin-4-tetradecanoate hydrochloride (I), etc.

EXAMPLE 12 Lincomycin-4-palmitate hydrochloride (1) A solution of 100 g. of lincomycin-Z-palmitate hydrochloride (IIb) in 200 ml. of absolute methanol is treated with 75 ml. of 6.6 N sodium hydroxide. After about 75 seconds the solution is neutralized with 76 ml. of 6.6-

N hydrochloric acid. The solvent is removed under vacuum at 40 C. The residual white solid is dissolved in 300 ml. of water with heating and on cooling crystallization occurs. The crystalline mixture containing 49.6 g. of lincomycin -2-, -3- and -4- palmitates is isolated and recrystallized from 1000 ml. of acetonitrile. The solids weighing 26.2 g. are removed by filtration and the filtrate, now enriched in the 4-palmitate, is taken to dryness at 60 C. under vacuum. An oily phase is decanted, while hot, from the white residual solid and the solid dissolved in a mixture of 300 ml. ether and 300 ml. of pH 5 buflfer (0.5 N phosphate-citrate). The ether phase is dried with sodium sulfate and gaseous hydrogen chloride introduced slowly to precipitate lincomycin-4-palmitate hydrochloride (I). Aliquots of the ethereal phase are analyzed by gas chromatography and just suflicient hyldrogen chloride introduced to precipitate the lincomycin-4-palmitate ester (1). The 2- and 3-palmitates remain in solution. The precipitate weighing 0.65 g. is isolated and dried under vacuum for about 24 hours and then equilibrated with the laboratory atmosphere.

Ahalysis.-Calcd. for C34H65N2O7SC1 (percent): C, 59.93; H, 9.62; N, 4.11. Found (corrected from H O content) (percent): C, 60.20; H, 9.41; N, 4.20.

What is claimed is:

1. A process for preparing a compound selected from the group consisting of the free bases and acid salts of a compound of the formula wherein R is alkyl of from one through six carbon atoms, R, is selected from the group consisting of alkyl of from one through eight carbon atoms, cycloalkyl of from three through eight carbon atoms and aralkyl of up to twelve carbon atoms, R is alkyl of from one through eight carbon atoms, Ac is the acyl radical of a hydrocarbon carboxylic acid of from two through eighteen carbon atoms and X is selected from the group consisting of chlorine, bromine and iodine, which comprises the steps of:

(1) mixing a corresponding compound of the formula wherein R, R R and X have the same meaning as above, with a 2 to,30 molar excess of a compound selected from the group consisting of tetraalkyldisilizane and hexaalkylidilazane, where alkyl is an alkyl radical of 1 through 4 carbon atoms, to yield a corresponding compound of the formula wherein Ac, n, R, R ,'R R and X have the same meaning as above;

(3) mixing a thus produced corresponding compound resulting from Step (2) With an organic carboxylic acid having a pKa of from about 3 to about 6 to yield a corresponding compound of Formula I, above.

2. A process in accordance with claim 1 wherein the starting material of Step (1) is 7(S)-chloro-7-deoxylincomycin (IV) and the product of Step (3) is 7 (S)-chloro- 7-deoxylincomycin-4-hexanoate hydrochloride (I).

3. A process for preparing a compound selected from the group consisting of the free bases and acid addition salts of a compound of the formula wherein R is alkyl of from one through six carbon atoms, R; is selected from the group consisting of alkyl of from one through eight carbon atoms, cycloalkyl of from three through eight carbon atoms and aralkyl of up to twelve carbon atoms, R is hydrogen, Ac is the acyl radical of a hydrocarbon carboxylic acid of from two through eighteen carbon atoms and X is selected from the group consisting of chlorine, bromine and iodine, which comprises the steps of 1) mixing a corresponding compound of the formula wherein R, R and X have the same meaning as above and Y is protective group removable by hydrogenolysis, with a 2 to 30 molar excess of a compound selected from the group consisting of tetraalkyldisilizane and hexaalkyldisilizane, where alkyl is an alkyl group of from 1 through 4 carbon atoms, to yield a corresponding compound of the formula wherein R is alkyl of 1 through 4 carbon atoms, n is selected from the integers two and three and R, R X and Y have the same meaning as above; (2) mixing a thus produced corresponding compound resulting from Step (1) with a compound selected from the group consisting of an acyl halide and an acyl anhydride of a hydrocarbon carboxylic acid of from two through eighteen carbon atoms, in the presence of a tertiary amine base selected from the group consisting of pyridine, lower alkylpyridine, di-lower alkylamino and tri-lower alkylamine, to yield a corresponding compound of the formula Y I N KL}: 7 ii I SR 0s mo 21 having a pKa of from about 3 to about 6 to yield a corresponding compound of the formula V l a H U N M ACO o I on wherein R is alkyl of from one through eight carbon atoms, R; is selected from the group consisting of alkyl of from one through eight carbon atoms, cycloalkyl of from three through eight carbon atoms and aralkyl of up to twelve carbon atoms, R is alkyl of from one through eight carbon atoms and Ac is the acyl radical of a hydrocarbon carboxylic acid of from two through eighteen carbon atoms, which comprises the steps of 1) mixing a corresponding compound of the formula wherein R, R and R have the same meaning as above, with a 2 to 30 molar excess of a compound selected from the group consisting of tetraalkyldisilizane and hexaalkyldisilizane, where alkyl is an alkyl group of 22 from 1 through 4 carbon atoms, to yield a corresponding compound of the formula (H3 H (R,) SlO OSl (ag u wherein n is selected from the integers two and three, R, R and R have the same meaning as above and R is 1-40 alkyl;

(2) mixing a thus produced corresponding compound resulting from Step (1) with a compound selected from the group consisting of an acyl halide and an acyl anhydride of a hydrocarbon carboxylic acid of from two through eighteen carbon atoms, in the presence of a tertiary amine base selected from the group consisting of pyridine, lower alkylpyridine, di-lower alkylamine and tri-lower alkylamine, to yield a corresponding compound of the formula wherein Ac, n, R, R R and R have the same meaning as above:

(3) mixing a thus produced corresponding compound resulting from Step (2) with an organic carboxylic acid having a pK of from about 3 to about 6 to yield a corresponding compound of Formula I, above.

6. A process in accordance with claim 5 wherein the starting material of Step (1) is lincomycin (IV) and the product of Step (3) is lincomycin-4-hexanoate hydrochloride (I),

7. A process for preparing a compound selected from the group consisting of the free bases and acid addition salts of a compound of the formula wherein R and R have the same meaning as above and Y is a protective group removable by hydrogenolysis with a 2 to 30 molar excess of a compound selected from the group consisting of tetraalkyldisilizane and hexaalkyldisilizane, wherein alkyl is an alkyl group of from 1 through 4 carbon atoms, to yield a corresponding compound of the formula Y PH,

ACD

(is! la l u wherein Ac, n, R, R R and Y have the same meaning as above;

(3) mixing a thus produced corresponding compound resulting from Step (2) with an organic carboxylic acid having a pK of from about 3 to about 6 to yield a corresponding compound of the formula its:

wherein R, R and Y have the same meaning as above;

(4) removing the protective group, by hydrogenolysis,

from a thus produced corresponding compound resulting from Step (3) to yield a corresponding compound of Formula I, above.

8. A process in accordance with claim 7 wherein the starting material of Step (1) is 1'-desmethyl-1-carbobenzoxylincomycin and the product of Step (4) is 1'- desmethyllincomycin-4-hexanoate hydrochloride (I).

9. A process for preparing a compound selected from the group consisting of the free bases and acid addition salts of a compound of the formula wherein R is alkyl of from one through six carbon atoms, R, is selected from the group consisting of alkyl or from one through eight carbon atoms, cycloalkyl of from three through eight carbon atoms and aralkyl of up to twelve carbon atoms, R is selected from the group consisting of hydrogen and alkyl of from one through eight carbon atoms, Ac is the acyl radical of a hydrocarbon carboxylic acid of from two through eighteen carbon atoms and X is selected from the group consisting of hydroxy, chlorine, bromine and iodine, which comprises mixing a corresponding compound of the formula IIa AcD'

wherein R, R R Ac and X have the same meaning as above, in a non-hydroxylic solvent selected from the group consisting of (a) substituted amides, (b) sulfoxides, (c) chlorinated hydrocarbons, (d) nitriles, (e) ether-s, (f) esters, (g) ketones and nitroal'kanes with a strong acid having a =pK less than 2. 1.0. A process in accordance with claim 9 wherein the starting material'is 7(S)-chloro 7 deoxy1incomycin-3- hexanoate hydrochloride (11a) and the product is 7 (S)- chloro-7-deoxylincomycin 4 hexanoate hydrochloride 11. A process in accordance with claim 9 wherein the starting material is lincomycin-3-hexanoate hydrochloride (11a) and the product is 1incomycin-4-hexanoate hydrochloride (I). V

12. A process for preparing a compound selected from the group consisting of the free base and acid addition salts of a compound of the formula I 0 Ac!) 5 wherein R is alkyl of from one through six carbon atoms, R is selected from the group consisting of alkyl of from one through eight carbon atoms, cycloalkyl of from three through eight carbon atoms and aralkyl of up to twelve carbon atoms, 'R; is selected from the group consisting'of hydrogen and alkyl of from one through eight carbon atoms, Ac is the acyl radical of a hydrocarbon carboxylic acid of from two through eighteen carbon atoms and X is selected from the group consisting of hydroxy, chlorine, bromine and iodine, which comprises the steps of (1) mixing a corresponding compound of the formula wherein R, R R Ac and X have the same meaning as above, in chloroform with a tri-lower alkylamine to yield a mixture of corresponding 2-, 3- and 4-acyl compounds;

(2) separating from the mixture of compounds resulting from Step (1), a corresponding compound of Formula I, above. I 13. A process in accordance with claim 12 wherein the starting material of Step (1) is 7(S)-chloro-7-deoxylincomycin-3-hexanoate hydrochloride (IIa) and the product of Step (2) is 7(S)-ch1oro-7-deoxylincomycin-4- hexanoate hydrochloride (1).

14. A process in accordance with claim 12 wherein the starting material of Step (1) is lincomycin-3-hexanoate hydrochloride (11a) and the product of Step (2) is lincomycin-4-hexanoate hydrochloride (I).

15. A process for preparing a compound selected from the group consisting of the free base and acid addition salts of a compound of the formula wherein R is alkyl of from one through six carbon atoms, R is selected from the group consisting of alkyl of from one through eight carbonatoms, cycloalkyl of from three through eight carbon atoms and aralkyl of up to twelve carbon atoms, R is selected from the group consisting of hydrogen and alkyl of from one through eight carbon atoms, Ac is the acyl radical of a hydrocarbon carboxylic acid of from two through eighteen carbon atoms and X is selected from the group consisting of hydroxy, chlorine, bromine and iodine, which comprises the steps of (l) mixing a corresponding compound of the formula R: 'L ca,

a cN-- a l! o In;

OAc

I i t \r t c ill gq R 3 I AcO 5 0 Ron SR wherein R is alkyl of from one through six carbon atoms, R is selected from the group consisting of alkyl of from one through eight carbon atoms, cycloalkyl of from three through eight carbon atoms and aralkyl of up to twelve carbon atoms, R is selected from the group consisting of hydrogen and alkyl of from one through eight carbon atoms, Ac is the acyl radical of a hydrocarbon carboxylic acid of from two through eighteen carbon atoms and X is selected from the group consisting of hydroxy, chlorine, bromine and iodine, which comprises the steps of (l) mixing a corresponding compound of the formula R a it I y c H N 1 ii! k on wherein R is alkyl of from one through eight carbon atoms, R is selected from the group consisting of alkyl of from one through eight carbon atoms, cycloalkyl of from three through eight carbon atoms and aralkyl of up to twelve carbon atoms, R is selected from the group consisting of hydrogen and alkyl of from one through eight carbon atoms R is selected from the group consisting of alkyl of from one through four carbon atoms, n is selected from the integers two and three, Ac is the acyl radical of a hydrocarbon carboxylic acid of from two through eighteen carbon atoms, and X is selected from the group consisting of chlorine, bromine and iodine.

21. A compound of claim 20 wherein R is methyl, R is trans-n-propyl, R is methyl, R is methyl, n is three, Ac is hexanoyl and X is 7(S)-chloro, namely, 7(S)- chloro-7-deoxylincomycin-4-hexauoate-2,3-bis (trimethylsilyl) ether.

22. A compound selected from the group consisting of the free bases and acid addition salts of a compound of the formula CH3 H (R Si0- wherein R is alkyl of from one through eight carbon atoms, R is selected from the group consisting of alkyl of from one through eight carbon atoms, cycloalkyl of from three through eighth carbon atoms and aralkyl 28 of up to twelve carbon atoms, R is selected from the group consisting of hydrogen and alkyl of from one through eight carbon atoms, R is selected from the group consisting of alkyl of from one through four 7 carbon atoms, 11 is selected from the integers two and three, and Ac is the acyl radical of a hydrocarbon carboxylic acid of from two through eighteen carbon atoms. 23. A compound of claim 22 wherein R is methyl, R

0 is trans-n-propyl, R is methyl, R is methyl and n is three,

namely, lincomycin 4 hexanoate, 2,3,7-tris-(trimethy1- silyl) ether.

References Cited UNITED STATES PATENTS 

